7 Nov 2017 FDA VRBPAC: Pfizer’s S. aureus vaccine — do results in one population generalize? (Part 2 of 3)

Addendum: This is the second in a 3-newsletters series on this topic. Go here for the first newsletter and here for the final newsletter. Finally, the results of the STRIVE trial have been published as Hassanzadeh et al. in Clinical Infectious Diseases, ciad218, https://doi.org/10.1093/cid/ciad218.

Dear All: 

wrote on 19 Oct 2017 about the meeting on 7 Nov 2017 of the Vaccines and Related Biological Products Committee (VRBPAC) at White Oak to discuss Pfizer’s investigational Staphylococcus aureus vaccine intended for pre-surgical prophylaxis in elective orthopedic surgical populations. I noted before, we’ve had prior debates on this topic that have revolved around these questions:

  1. Can you use eradication of carriage as a measure of the value of prophylactic agent?
  2. How big does the study have to be if you must show reduction in a serious (non-trivial) clinical infection?
  3. In what population can you do this?

As I indicated previously, the answers to these questions to date have been NO, VERY LARGE, and NOT SURE.  A briefing book by FDA is now posted online and allows us to see under the hood. In brief, the VRPBAC will focus on the problem of questions (2) and (3) from above as follows:

  1. Pfizer have initiated a Phase 3 trial of their vaccine in a population with the highest rate of surgical infection (despite good care) they could find: open, posterior approach, multi-level, instrumented, spinal fusion orthopedic surgery.
  2. The post-op infection rate in this population is 1.4%. Based on this, Pfizer have been running a trial that (per clinicaltrials.gov) will enroll over 3 years about 2,600 subjects at 1:1 vaccine:placebo.
  3. Per the briefing book, Pfizer estimate this sample size gives them an 88% power to detect a 70% (or better) reduction in post-op infection rate. This would correspond to a fall from 1.4% to 0.42%.
  4. Pretty easy so far on the logic, but now for the core question of the day: If there are no safety issues, can these data in one orthopedic procedure be generalized to other orthopedic procedures?
  5. On this point, the FDA briefing book notes that “Pfizer states that while the rates of invasive S. aureus disease across other elective orthopedic surgical populations are significant, they are low (~0.25% to ~0.5% within 90 days of surgery). Therefore, Pfizer states that conducting a randomized, placebo-controlled clinical endpoint efficacy trial that includes other elective orthopedic surgical populations would make the conduct of such a trial operationally impractical.”
  6. I agree here! My simple man’s sample size calculations quickly take me from the already substantial ~1,300/arm of the current study to sizes beyond 10-20,000 per arm.

Absolutely fascinating and I am delighted to see FDA and Pfizer bringing this great question into a public forum: a path forward in non-geologic time with non-infinite sample sizes is going to be needed if want to have more than a handful of tools of this type.

The FDA briefing book is excellent and I commend it to you … it provides a good summary of past (failed) efforts in this area as well as further details on the key question to be discussed.

All best wishes, –jr

John H. Rex, MD | Chief Medical Officer, F2G Ltd. | Expert-in-Residence, Wellcome Trust. Follow me on Twitter: @JohnRex_NewAbx. See past newsletters and subscribe for the future: http://amr.solutions/blog/

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